Paliperidone ketone

ABSTRACT

A compound of formula (7.2) or an acid addition salt thereof. 
                         
The compound can be used as a reference standard for monitoring the presence thereof in a paliperidone sample, including monitoring the completion of a paliperidone reaction. Reduction in the amount of the compound in paliperidone can be achieved by crystallization in the presence of a hydride reductant.

This application claims the benefit of priority under 35 U.S.C. §119(e)from U.S. Provisional application Ser. No. 61/080,088, filed Jul. 11,2008; the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Paliperidone, or 9-hydroxyrisperidone (chemically:(±)-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)ethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one)of the formula (I):

is a major human metabolite of the known antipsychotic drug risperidoneand is itself an antipsychotic. It is marketed in tablets for oraladministration under the brand name INVEGA™ (Janssen, L. P.) fortreatment of schizophrenia. Paliperidone has one centre of opticalactivity (the carbon in the 9-position); both enantiomers are known butthe marketed compound is a racemate.

Paliperidone (including enantiomeric forms thereof) has been disclosedin EP 368388 (U.S. Pat. No. 5,158,952). The same document discloses alsoesters of paliperidone with carboxylic acids having the formula (II)(R′═C₁₋₁₉ alkyl)

A preferred ester compound (II) is paliperidone palmitate, which iscurrently under development for use in injectable compositions withprolonged action.

Various processes for making compounds of formula (I) and (II) have beengenerally disclosed in the EP 368388 and in later documents. One processis based on an alkylation of a 3-piperidinyl 1,2-benzisoxazole of theformula (2) with the compound of formula (1.1), wherein R is hydrogen orC1-C20 acyl group and A represents an appropriate leaving group such as,for example, halo, e.g., chloro, bromo or iodo; sulfonyloxy, e.g.,methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy,4-methylbenzenesulfonyloxy and the like leaving groups:

Another known process is based on the reaction of the same compound(1.1) with an oxime compound (3), wherein L is a reactive leaving group,followed by the ring closure of the isoxazole ring on the intermediate(4):

Furthermore, the esters of formula (II) may be prepared by acylatingpaliperidone (I) by an acylation agent (e.g. acyl halide or acylanhydride).

The compounds of the general formula (1.1) are valuable intermediates inmaking paliperidone (I) as well as the paliperidone esters of theformula (II). A typical example of the intermediate of the generalformula (1.1) is the compound3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneof the formula (1a)

The precise reaction mechanisms including unintended side-reactions,have not, however, been fully elucidated for the above-mentionedreaction schemes. It would be desirable to improve the control, yield,and/or purity of a process for making paliperidone or its esters.

SUMMARY OF THE INVENTION

Applicants have discovered that the synthesis of paliperidone accordingto the above prior art schemes, as well as the transformation thereofinto pharmaceutical dosage forms (e.g. tablets or solutions), suffersfrom a disadvantage in that a certain amount of a keto-compound offormula (7.2) is formed as a side product.

To improve the manufacturing and control processes related topaliperidone, it is desirable to have the compound (7.2) prepared in anisolated state with a sufficient and defined purity, e.g., for use as areference material during the analytical control of the synthetic and/orpurification process as well as in the analytical control of the purityof the paliperidone product and its various pharmaceutical dosage forms.

Accordingly, a first aspect of the present invention is directed to acompound of formula (7.2) or an acid addition salt thereof

in an isolated state having a purity of greater than 50%, such asgreater than 80%, preferably greater than 95%.

A second aspect of the present invention is directed to a process, whichcomprises crystallizing crude paliperidone in the presence of a hydridereductant to form paliperidone essentially free from a compound offormula (7.2). Preferably, the hydride reductant is sodium borohydride.Typically, the hydride reductant is present in an amount of 0.01 to 0.5molar equivalents based on the molar amount of the crude paliperidone.

A third aspect of the present invention relates to a process, whichcomprises assaying a paliperidone sample for the presence of a compoundof formula (7.2). The paliperidone sample can be taken from a crudereaction mixture or from a presumed pharmaceutical grade paliperidonelot, e.g., received API. Taking the paliperidone sample during thesynthetic reaction allows for controlling the reaction based on theresult of the assaying; e.g., terminating the reaction if the amount ofthe compound of formula (7.2) in the paliperidone sample is below apredetermined threshold value. Alternatively, taking the paliperidonesample from a presumed pharmaceutical-grade lot or batch or paliperidoneallows for quality testing and/or reprocessing of API. In oneembodiment, the assaying results from the sample lead to:

-   -   a) accepting the presumed pharmaceutical-grade paliperidone lot        as pharmaceutical grade if the amount of the compound of formula        (7.2) in the paliperidone sample is below a predetermined        threshold value; or    -   b) rejecting the presumed pharmaceutical-grade paliperidone lot        as pharmaceutical grade if the amount of the compound of formula        (7.2) in the paliperidone sample is at or above a predetermined        threshold value.        The rejected lot can then be subjected to crystallization in the        presence of a hydride reductant to remove/reduce the compound of        formula (7.2) and form a new presumed pharmaceutical-grade        paliperidone lot.

The present invention also relates to the use of the compound of formula(7.2) in its isolated state as a reference material for monitoringand/or improving the course of a process for making paliperidone and/orfor purification of reaction mixtures or raw materials comprisingpaliperidone.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the discovery of an isolated, includingsolid state form, of the compound of formula (7.2) and to various usesthereof in the synthesis of paliperidone and its acyl derivatives of thegeneral formula (1).

The formula (7.2) as used herein also embraces acid addition saltsthereof.

Many processes of making paliperidone and its pharmaceutical dosageforms, as well as the storage of paliperidone in its isolated state andthe pharmaceutical dosage forms, suffer from the disadvantage of formingan impurity, which was discovered and identified by the presentinventors as a compound of the formula (7.2). Without wishing to bebound by theory, it is thought that this compound may be formed byaerial oxidation of the paliperidone or may be formed as a side productupon hydrolysis of an enamine (5).

The enamine (5) may result from the condensation of an excess of thecompound (2) or (3) with the reactive hydroxyl-group in the compound(1.1). The hydrolysis of the enamine (5) into (7.2) could occur duringsubsequent reaction steps.

Regardless of how it is formed, the presence of the compound of theformula (7.2) as a side-product in the paliperidone synthesis isundesirable. Being able to detect the compound of formula (7.2), controlreaction conditions to minimize its content and/or to convert it topaliperidone is thus desirable.

Compound (7.2) in an “isolated state” refers to any product comprisingthe compound (7.2) having a purity greater than 50%, such as greaterthan 80%, and preferably greater than 90% of the compound (7.2). The“purity” of compound (7.2) relates to the presence or absence ofresidual solvents and reagents as well as structurally relatedimpurities. For example, a compound (7.2) in an isolated state having apurity of greater than 85% may comprise less than 5% of residualsolvents and reagents from its synthesis and less than 10% ofstructurally related impurities.

It was discovered that the compound of the formula (7.2) in an isolatedstate may be prepared by oxidation of paliperidone by a suitableoxidant, e.g., by a commercially available Dess-Martin periodinate ofthe below formula.

With this Dess-Martin periodinate oxidation agent, the reaction proceedsin a corresponding suitable inert solvent, such as in a hydrocarbon or ahalogenated hydrocarbon solvent, and at essentially ambient temperature.

Another useful oxidation agent is sodium hypochlorite (NaClO), and acorresponding suitable inert solvent is preferably a polar aproticsolvent, e.g., acetonitrile or dimethyl formamide.

Still other useful oxidation agents include chromium trioxide andchromium (VI) salts, pyridinium chlorochromate, dimethyl sulfoxide(including in combination with dicyclohexylcarbodiimide, phosphoruspentoxide, oxalyl chloride, or trifluoroacetanhydride), manganesedioxide, silver carbonate, and acetone with potassium/aluminiumalkoxide, etc.

The product (7.2) may be isolated by conventional means, e.g., byevaporation of the solvent, and further purified, e.g., by arecrystallization from a suitable crystallization solvent.

In another process, the isolated form of the compound (7.2) may also beprepared by condensation of a compound of the formula (7)

with the compound (2) or (3) similarly as indicated above for thecompound (1.1). The starting compound of the formula (7) may be preparedfrom the compound (1.1), preferably from the compound (1a), by areaction with a suitable oxidant, e.g., by Dess-Martin periodinate,under essentially same conditions as indicated above.

In yet another process, the isolated form of the compound (7.2) may beprepared by a reaction of an aldehyde of the formula (8)

with peracetic acid. The aldehyde (8) may be obtained by a processdisclosed in U.S. provisional application Ser. No. 60/952,376, filedJul. 27, 2007, the entire contents of which are incorporated herein byreference.

The isolation of the compound (7.2) from a reaction mixture provides thecompound (7.2) in a stable and handleable form with a defined quality,allowing various practical uses thereof.

For example, the isolated form of the compound (7.2) may serve as areference standard in an analytic method for monitoring a chemicalprocess yielding paliperidone or for monitoring stabilitycharacteristics of the obtained paliperidone product. A suitableanalytical method is HPLC, though other conventional analyticaltechniques such as TLC can also be used. The use as a reference standardcontemplates the preparation of a reference sample of the compound (7.2)in sufficient purity that the qualitative and quantitativecharacteristics thereof (e.g., in HPLC, retention time and a peak areaof a defined amount of the reference material) can be determined. Thesecharacteristics can then facilitate the identification and/orquantification of the compound (7.2) in a sample. Thus the isolated formof the compound (7.2) facilitates assaying for its presence in varioussamples of paliperidone. A “paliperidone sample” is a sample taken fromany substance or material that contains paliperidone; for examplesamples taken from a crude reaction mixture wherein paliperidone isbeing or has been synthesized, a solid pharmaceutical-gradepaliperidone, a pharmaceutical dosage form (tablet, etc.) that containspaliperidone as an active ingredient, etc. By assaying the paliperidonesample, the relative or absolute amount of the compound (7.2) in thetested sample is determined and, accordingly, corresponding adjustmentin the production, purification or storage can be made.

One example of the use of assaying relates to the synthesis ofpaliperidone. A paliperidone sample can be taken from a crude reactionmixture at the end of the reaction to determine the level of thecompound (7.2) impurity as a quality control determination and/or todetermine if further processing should be undertaken to reduce theamount of the compound (7.2). Likewise, a sample can be taken during thereaction and the result of the assay used to assist in controlling thereaction. The term “controlling” generally means adjusting the durationof the reaction, although “controlling” could also mean adjusting thetemperature, pressure, amount of reducing agent, etc. In a simpleexample, the reaction is terminated once the amount of compound (7.2) isbelow a predetermined level; e.g. less than 5% more typically less than2%, as determined by the assaying step. The reaction can be monitoredsuch as by HPLC in order to determine when the predetermined thresholdhas been met.

Essentially any paliperidone synthetic process can be subject to theassaying. In a preferred embodiment, the reaction involves a conversionof risperidone to paliperidone via a reductive deoximation of an oximeas more fully described in U.S. provisional application Ser. No.61/080,072, filed Jul. 11, 2008, the entire contents of which areincorporated herein by reference. In this co-pending application, aprocess according to the scheme below may be monitored for the presenceof the intermediate compound (7.2) and terminated after the content ofthe compound (7.2) in the reaction mixture drops under a predeterminedthreshold, e.g., below 2%.

Another example of the use of the assaying step relates to the stabilityand/or purity of paliperidone in solid form, isolated form, or insolution. Based on the assaying result, the storage conditions may beadjusted or revised in such a way that the content of the compound (7.2)in the paliperidone product does not exceed a predetermined threshold.

In a particular embodiment, a paliperidone sample is taken from apresumed pharmaceutical-grade paliperidone lot and assayed for thepresence of the compound of formula (7.2). The term“pharmaceutical-grade” means that the lot or batch of paliperidone has apurity of at least 98%, preferably greater than 99%. The term “presumed”refers to a lot that is thought to be pharmaceutical-grade, e.g., afteran API (active pharmaceutical ingredient) manufacturer makes such a lot,after such a lot is stored, after such a lot is shipped, or after athird party received such a lot and desires to confirm the puritythereof, etc. Based on the assay of the sample, the lot can be acceptedor rejected as being pharmaceutical-grade, at least with respect to thecompound of (7.2). Thus, a lot would be accepted as pharmaceutical gradeif the sample has an amount of the compound (7.2) below a predeterminedthreshold, e.g. less than 1% and more typically less than 0.5% and evenless than 0.2%. Alternatively, a lot would be rejected aspharmaceutical-grade if the amount of the compound (7.2) is above apredetermined threshold. It should be noted that a pharmaceutical-gradelot would likely have additional purity requirements and thus theacceptance of the lot based on this assay would not necessarily be, noris it required to be, the only criterion for acceptance. A rejected lotcan be reprocessed to reduce the impurities to form a new presumedpharmaceutical-grade paliperidone lot, if desired, and subjected to theassaying process again.

Likewise dosage forms containing paliperidone can also be assayed andmonitored for the presence of the compound (7.2). As the compound (7.2)may be a product of aerial oxidation, the process of making dosage formsof paliperidone (tablet, etc.) as well as storing these forms prior toactual use may cause the formation of the compound of formula (7.2).Accordingly, samples of paliperidone dosage forms may be assayed tomonitor the presence of the compound (7.2) with the goal to adjust theprocess and/or storage conditions to minimize the formation of thecompound(7.2) or to simply judge the quality and continued acceptabilityof the dosage form after a certain shelf-life.

An additional use of the compound (7.2) of the present invention is itsconversion into paliperidone. The ability to convert the compound (7.2)via a reductant into paliperidone can be used to aid in the purificationand/or isolation of paliperidone. In one process, the impurepaliperidone is crystallized from a crystallization medium comprising asolvent and a hydride reductant, advantageously sodium borohydride. Themolar amounts of the reductant may typically vary from 0.01 to 0.5equivalents; its actual amount may be adjusted in respect to theactually present compound (7.2) in the crude paliperidone. The smallamounts of the compound (7.2) present in the impure paliperidonematerial are converted within the crystallization process intopaliperidone, so that the purity of the obtained product issignificantly enhanced. In certain embodiments, the content of thecompound (7.2) in a paliperidone sample after this kind of apurification process could be below the limit of detection by HPLC.Thus, after one or more such crystallization processes, the resultingpaliperidone is essentially free from the compound (7.2), i.e., containsless than 5%, such as less than 3% or 2%, preferably less than 1%, andmore preferably less than 0.2% of the compound (7.2). Thecrystallization is a convenient way to reprocess a rejected lot ofpaliperidone and thus create a new presumed pharmaceutical-grade lot ofpaliperidone as described above in connection with the assayingprocesses. Depending on the crystallization conditions, the solidpaliperidone may be obtained in various crystalline forms, e.g., informs disclosed in the patent application WO2008/021342.

The invention will be further described with reference to the followingnon-limiting examples.

EXAMPLES Example 1 Process for Making the Keto-compound (7.2)

5.0 g of paliperidone was dissolved in 17.0 ml of dichloromethane. 5.38g of Dess-Martin periodinane (DMP) and 0.63 ml of sulfuric acid (96%)were added into the reaction mixture and it was stirred at 0° C. for 30minutes and at room temperature (25° C.) for 4 hours. Next amount of1.28 g of Dess-Martin periodinane was added at T=4 h 15 min. After 6hours the homogenous reaction mixture was diluted with 100 ml ofdichloromethane and poured into 200 ml of saturated aqueous NaHCO₃solution containing 10 g of sodium thiosulfate (Na₂S₂O₃). The mixturewas stirred for 20 min. The dichloromethane layer was washed with 150 mlof saturated aqueous NaHCO₃ solution, 2×150 ml of water, 150 ml ofbrine, dried (MgSO₄), filtered and evaporated on rotavap. The yield ofdark yellow crude product: is 2.57 g (51.6%).

The crude product was redissolved in hot acetonitrile, solid productobtained after cooling was filtered out and discarded, and the solventwas evaporated. The evaporation residue was triturated twice with hotacetonitrile to obtain a product with HPLC purity (IN) 87.7%.

Example 2 Process for Making of Keto Compound (7.2)

4.2 g of paliperidone was stirred with 50 ml of AcOH and 12.6 ml ofCH₃CN was added at RT. The mixture becomes clear. The solution wascooled to 0° C. and 8.4 ml of solution NaOCl (content active chlorine140-150 g/1000 ml) was dropwise added in 1 min. The internal temperaturewas increased to 6° C. After 17 min the cooling bath was removed andinternal temperature increased to 22° C. After 90 min reaction mixturewas poured into 700 ml of brine at 0° C. The solids were filtered bysuction, dissolved in acetone and solvent was evaporated (200-20 mbar,40° C.). Solid material was obtained (slight brown color) with HPLCpurity (IN) 62% with yield 76%.

Example 3 Process for Making the Keto-compound (7.2)

4.0 g of compound (8) was added portionwise into 40 ml of water and 5.1ml of peracetic acid during 10 min at 35° C. The internal temperatureincreased from 35° C. to 40° C. The solid material was dissolvedimmediately. Into the reaction mixture, 50 ml of dichloromethane wasadded after 10 additional minutes. The mixture was neutralized by 20%solution of NaHCO₃ to pH-7.3. The layers were separated and organiclayer washed with 2×40 ml of water, dried by solid sodium sulphate andfiltered with activated charcoal over celite. The solvent was evaporated(30 mbar, 40° C.). The yield of white foamy material is 2 g (52%),purity 64% (HPLC IN).

Example 4 Purification Process for Removing the (7.2) from Paliperidone

40 g paliperidone (purity 98.6%, content of the impurity (7.2) is 0.35%)was dissolved in a mixture of 260 ml of water, 260 ml of isopropanol and6.76 g of CH₃COOH (1.2 equivalents) at 50° C. in a nitrogen atmosphere.The mixture was cooled to 30° C. and 11.5 ml of 2.025M aqueous NH₃ (0,25equivalents) and 40 ml of the borohydride solution (0.106 g of NaBH₄ +20ml of water +20 ml of isopropanol +one drop of 10% NaOH) was added. Themixture was stirred for 30 minutes at 30° C. Then, 44.5 ml of 2.025Maqueous NH₃ (0.95 equivalents) was added. The suspension was stirred for1 hour. The crystals were filtered off and washed with 2×80 ml ofmixture (water:isoPrOH=1:1). Yield: 33.39 g (83.5% of the theoreticalyield) of the crystallized paliperidone having an HPLC purity of 99.7%and no detectable amount of (7.2).

Each of the patents, published patent applications, and provisionalapplications mentioned above are incorporated herein by reference. Theinvention having been thus described it will be obvious that the samemay be varied in many ways and all such modifications are contemplatedas being within the scope of the invention as defined by the followingclaims.

1. A compound of formula (7.2) or an acid addition salt thereof

in an isolated state having a purity of greater than 50%.
 2. Thecompound according to claim 1, wherein said isolated compound has apurity of greater than 80%.
 3. The compound according to claim 2,wherein said isolated compound has a purity greater than 95%.
 4. Aprocess, which comprises crystallizing crude paliperidone in thepresence of a hydride reductant to form paliperidone essentially freefrom a compound of formula (7.2)


5. The process according to claim 4, wherein said hydride reductant issodium borohydride.
 6. The process according to claim 4, wherein thehydride reductant is present in an amount of 0.01 to 0.5 molarequivalents based on the molar amount of the crude paliperidone.
 7. Aprocess, which comprises assaying a paliperidone sample for the presenceof a compound of formula (7.2).


8. The process according to claim 7, wherein said paliperidone samplewas taken from a crude reaction mixture.
 9. The process according toclaim 8, wherein said paliperidone sample was taken during said reactionand said process further comprises controlling said reaction based onthe result of the assaying.
 10. The process according to claim 9,wherein said controlling comprises terminating said reaction if theamount of said compound of formula (7.2) in said paliperidone sample isbelow a predetermined threshold value.
 11. The process according toclaim 7, wherein said paliperidone sample was taken from a presumedpharmaceutical-grade paliperidone lot.
 12. The process according toclaim 11, which further comprises: a) accepting said presumedpharmaceutical-grade paliperidone lot as pharmaceutical grade if theamount of the compound of formula (7.2) in the paliperidone sample isbelow a predetermined threshold value; and b) rejecting said presumedpharmaceutical-grade paliperidone lot as pharmaceutical grade if theamount of the compound of formula (7.2) in the paliperidone sample is ator above a predetermined threshold value.
 13. The process according toclaim 12, wherein said rejected lot is subjected to crystallization inthe presence of a hydride reductant to form a new presumedpharmaceutical-grade paliperidone lot.
 14. A process of making thecompound of formula (7.2.) of claim 1, which comprises oxidizingpaliperidone with an oxidation agent to form said compound of formula(7.2).
 15. A process for making the compound of formula (7.2) of claim1, which comprises reacting an aldehyde of formula (8)

with peracetic acid to form said compound of formula (7.2).